REVIEW

CURRENT
OPINION What is new in the management of skin and soft
tissue infections in 2016?
Garyphallia Poulakou, Efthymia Giannitsioti, and Sotirios Tsiodras

Purpose of review
Skin and soft tissue infections (SSTIs) are the most frequent infectious cause of referrals to emergency
departments and hospital admissions in developed world, contributing to significant morbidity and
healthcare expenditures. We sought to review recent literature covering epidemiology and management of
SSTIs.
Recent findings
Incidence trends of SSTIs were increasing worldwide with Staphylococcus aureus and streptococci
predominating and methicillin-resistant S. aureus (MRSA) posing additional challenges, because of high
rates of treatment failure and relapse. Development of new antimicrobials was associated with an appraisal
of regulatory definitions and endpoints. Prediction of clinical response can be very tricky, because of
variable risk factors for recurrence or treatment failure, depending mostly on the host. Precise indications
for new antimicrobials should be established; their integration into clinical practice algorithms may serve
reduction of unnecessary admissions, overtreatment and total costs.
Summary
New antimicrobials with activity against MRSA have been recently launched. Long-acting agents, mainly
oritavancin and dalbavancin, provide the opportunity of single-dose treatment and early discharge. Further
outpatient treatment options include new per os antibiotics such as oxazolidinones. Validated assessment
tools are urgently needed to support decision-making toward rational resource utilization and delivery of
optimal treatment.
Keywords
drainage, methicillin-resistant Staphylococcus aureus, new antimicrobials, relapse, skin abscess

INTRODUCTION of SSTIs, from 23.2 in 2000 to 62.7 in 2006 per 100

Skin and soft tissue infection (SSTI) represents one of
the most common causes of referral to the emer-
gency department (ED) and one of the most
common infectious causes of hospital admissions. A
strong recent increasing incidence trend was mainly
attributed to the expansion of aging population
with comorbidities and the emergence of com-
munity-acquired methicillin-resistant Staphylococ-
cus aureus (CA-MRSA) [1,2]. In the United States,
according to the National Hospital Ambulatory
Medical Care Survey database ED, visits for uncom-
plicated SSTIs (uSSTIs) almost doubled between
1993 and 2005 (from 1.35 to 2.98%, P < 0.001)
[3]. In addition, according to the Healthcare Cost
and Utilization Project National Inpatient Sample,
hospital admissions for SSTIs in the United States
increased by 30% between 2000 and 2004, most
notably because of superficial infections in adults
less than 65 years of age [4]. Children’s Inpatient
Databases, showed a 2.5-fold increase in incidence
000 pediatric patients [5]. Similarly, a three-fold
increase in admissions because of abscesses,
furuncles, carbuncles and cellulitis was recorded
in the UK between 1990 and 2004 [6]. The increased
prevalence of methicillin-resistant Staphylococcus
aureus (MRSA) has introduced additional thera-
peutic challenges in both hospital and outpatient
settings. SSTIs have a large array of clinical features
ranging from superficial infections of the skin to
bacteremic and possibly life-threatening infections
Fourth Department of Internal Medicine, Athens National and Kapodis-
trian University, School of Medicine, Attikon University General Hospital,
Athens, Greece
Correspondence to Garyphallia Poulakou, Fourth Department of Internal
Medicine, Athens National and Kapodistrian University, School of Medi-
cine, Attikon University General Hospital, 1 Rimini st 12462, Athens,
Greece. Tel: +302105831990; e-mail: gpoulakou@gmail.com
Curr Opin Infect Dis 2017, 30:158–171
DOI:10.1097/QCO.0000000000000360

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 Management of skin and soft tissue infections in 2016 Poulakou et al.

CLASSIFICATION AND EPIDEMIOLOGY

KEY POINTS
 SSTIs represent a considerable percentage of infectious
causes of referral to an ED and hospital admission.
 SSTIs caused by methicillin-resistant S. aureus pose an
additional challenge to clinicians, because of high
rates of treatment failure and relapse.
 As a handful of new antimicrobials has been launched
for the treatment of SSTIs, further data from real-life use
are warranted to define their precise position in clinical
algorithms, taking into consideration the need of
hospital admission and total cost.
 The cost-effectiveness and clinical performance of the
newly launched long-acting antibacterials dalbavancin
and oritavancin have to be evaluated in prospective
trials.
 Novel approaches (phages) and novel antimicrobial
classes (pleuromutilins) will probably be soon available
in clinical practice.
[1,7]. This article will review the literature published
between June 2015 and December 2016, focusing on
epidemiology and management of SSTIs and taking
into consideration the ‘hot topics’ that were ident-
ified in a recent publication from experts of the SSTI
Working Group of the International Society of Che-
motherapy [8].
There are several classification approaches of SSTIs
in the literature, with none of them being univer-
sally adopted. Two comprehensive definitions pro-
posed by the Infectious Diseases Society of America,
namely uSSTIs and complicated SSTIs (cSSTIs) and
based on the extent of the infection and the need for
surgical intervention, are shown in Table 1 [7,9,10].
A breakthrough in the regulatory procedures of new
antibacterials for SSTIs has been accomplished with
the introduction of the definition of Acute Bacterial
Skin and Soft Structure Infection (ABSSSI) by the
Food and Drug Administration in 2013 [10]. ABSSSI
is defined as a bacterial infection of the skin with a
lesion size area of at least 75 cm2, with variable
clinical presentations presented in Table 1. In
addition, a new primary endpoint was introduced,
referred to as early assessment of clinical response: at
least 20% reduction in lesion size at 48–72 h com-
pared with baseline. The traditional response at test
of cure (7th–10th day) was then proposed as secon-
dary endpoint [10].
An important contemporary study from United
States explored incidence of SSTIs between 2005 and
2010, using ambulatory and inpatient data of more
than 48 million persons-years aged 0–64 years from
the HealthCore Integrated Research Database. SSTI
incidence, with peak at the age of 45–64 years, was
approximately 4.8 SSTIs per 100 person years and

Table 1. Definitions of complicated and uncomplicated skin and soft tissue infections and acute bacterial skin and soft structure
infections
Uncomplicated SSTI Complicated SSTI ABSSSI

Superficial infections Deep soft tissue infection SSTIs with lesions with a minimum surface area of 75 cm2
Cellulitis Lesion requiring surgical procedure Criteria
Erysipelas Large abscesses Erythema and/or induration extending 5 cm
from the peripheral margin of the infection
Folliculitis Infected postoperative wounds Systemic signs of infection (such as fever)
Furunculosis Infected burns (and/or) proximal lymphadenopathy
Ecthyma Infected chronic ulcers Types of infections included
Impetigo Necrotizing infections Cellullitis, erysipelas
Infections that can be treated Rapidly expanding infections Major cutaneous abscesses
with surgical incision alone
Small abscesses Bacteremic infections and/or Wound infections
with septic shock
Absence of significant Significant underlying diseases or Excluded: impetigo and minor cutaneous abscess,
comorbidities comorbidities compromising animal or human bites, burns, necrotizing fasciitis
treatment outcomes and myonecrosis, diabetic foot infection, chronic
wound infection, ecthyma gangrenosum, underlying
osteomyelitis or septic arthritis, concurrent medical
conditions that would obscure evaluation of
outcome (i.e. neutropenia)

SSTI, skin and soft tissue infection.

Adapted from [7,9,10].

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Skin and soft tissue infections

remained stable through the observed period, being,
however, almost two-fold of that of urinary tract
infections and 10-fold of that of pneumonia. Most
SSTIs (95%) were treated in the ambulatory setting,
the majority (57.3%) being classified as abscesses
or cellulitis, with complications rates (i.e. sepsis,
bacteremia, osteomyelitis, myositis and gangrene)
of 0.93 and 16.92% for ambulatory and hospitalized
&&
patients, respectively [11 ]. Therefore, the increas-
ing trends in the incidence of SSTIs observed in the
onset of the new millennium [2–4], mainly driven
by the emergence of CA-MRSA seem to have reached
a plateau, at least in United States.
In Europe, data from the European Centre for
Disease Prevention and Control estimated that 4%
of all healthcare-acquired infections (HAIs) reported
between 2011 and 2012 were SSTIs, with surgical-
site infections being the second most frequently
reported HAI (19.6%) [12]. Incidence of MRSA infec-
tions in Europe shows significant country variation
ranging from 0.9% (Netherlands) to 56.0% (Roma-
nia). An overall decreasing trend has been recorded,
with population-weighted mean percentage for
MRSA declining from 18.6% in 2011 to 17.4%
in 2014 [13]. An important epidemiologic study
highlighted the differences between European
and US CA-MRSA epidemiology, indicating highly
diverse distribution of Methicillin-sensitive Staph-
ylococcus aureus (MSSA) and MRSA clones with no
predominant circulating clone, no archetypical
USA300 CA-MRSA clone and Panton–Valentine
&
Leucocidine production in 24.9% of isolates [14 ].
The most frequently isolated gram-positive
pathogens in SSTIs are S. aureus (including MRSA),
followed by b-hemolytic streptococci; other strep-
tococci, enterococci and gram-negative bacteria
&&
may also be involved [10,15,16 ]. Depending on
the clinical setting, polymicrobial infections may be
&&
encountered (Table 2) [1,9,16 ]. An outbreak of
type emm59 invasive group A Streptococcus (iGAS)
disease was recognized in 2008 in Northwestern
Ontario, Canada; illicit drug use, alcohol abuse,
homelessness and hepatitis C infection were eluci-
dated as predisposing conditions [17]. Mycobacteria

Table 2. Risk factors for skin and soft tissue infections and particular pathogens

Risk factors Risk factors for SSTI Risk factors for Risk factors for SSTI
for SSTI by MRSA CA-MRSA by gram negatives

Trauma (laceration, abrasion, Previous colonization
crush, burn and so on)
Intravenous drug use Contact with colonized
persons
Human and animal bites Antibiotic treatment in the
previous 12 months
Conditions that predispose to Hospitalization in the previous
infection 12 months
Diabetes mellitus Previous infection by MRSA
Previous cellulitis Residence of long-term care
facility
Radical mastectomy with Recent travel in Latin America,
lymph node resection South East Asia and Africa
Saphenous vein harvesting Previous ICU admission
Neutropenia Cardiovascular disease
Hypogammaglobulinemia Diabetes mellitus
Chronic renal disease Peripheral vascular disease
Cirrhosis Chronic wounds
Alcoholism Immunosuppression
Chronic renal disease
Dialysis
Central venous catheters and
implantable devices
Intravenous drug use
Contact sports Surgical site infections
Military service Axillary cavity
Incarceration Gastrointestinal tract
Overcrowded housing Female genital tract
Poor hygienic conditions Inguinal area and perineum
Intravenous drug use Penetrating injury (Pseudomonas
aeruginosa)
Young children with Injury sustained in fresh water (Vibrio
daycare exposure vulnificus)
Injury sustained in salt water
(Aeromonas hydrophila)
Human bite (Eikenella corrodens)
Animal bite (Capnocytophaga sp,
Pasteurella multocida)
Diabetes mellitus
Cirrhosis
Intravenous drug use
Subcutaneous drug use

CA-MRSA, community-acquired MRSA; MRSA, methicillin-resistant Staphylococcus aureus; SSTI, skin and soft tissue infection.
&&
Adapted from [1,9,16 ].

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 Management of skin and soft tissue infections in 2016 Poulakou et al.
although rare should be considered in certain epi-
demiological scenarios; Mycobacterium abscessus is
being increasingly reported after aesthetic surgery
particularly in the context of medical tourism,
whereas Mycobacterium marinum can infect fish mar-
ket workers [18,19]. International travel has been
recognized as an important factor for severe MRSA
SSTI; imported MDR S. aureus had 1; 10 probability
of inadequate initial treatment. A recent study high-
lights the considerations posed by cross-border
transmission in returnees and the need for manage-
ment algorithms to increase likelihood of appropri-
&&
ate empirical treatment [20 ].
HIV infection, was shown as a strong predispo-
sion for relapsing SSTIs in one-third of patients
within 1 year in a recent cohort study; specific risk
factors of this population included nonhepatitis
liver disease, intravenous catheter presence, a
history of Intravenous drug use (IVDU) and non-
African-American race, but not low CD4þ cell count
&
[21 ]. Furthermore, opioid-related SSTI in United
States increased two-fold from 4 to 9 per 100,000
between 1993 and 2010, mostly affecting ages
between 20 and 40 years and in parallel with yearly
increase in price-per-gram-pure heroin [22].
ASSESMENT OF SEVERITY OF ILLNESS
AND RESPONSE TO TREATMENT
Skin infections are highly variable in presentation,
thus multiple severity-of-illness systems have been
proposed. Nevertheless, no one system has gained
universal acceptance, mainly because of overlap-
ping definitions of infections and severity strata
[9]. Validated severity of illness scoring is the corner-
stone for decision-making, relating to inpatient/
intravenous care or transition from i.v. to oral care.
The Clinical Resource Efficiency Support Team
(CREST) scoring system stratifies patients into four
classes (from I, least severe to IV, most severe) based
on the Standardized Early Warning Score. In a
single-center study in United States, CREST criteria
were retrospectively applied in 200 patients, the
majority of them being classified as class I or II.
Overtreatment, mainly because of unnecessary
inpatient i.v. antimicrobial treatment or broad spec-
trum coverage was identified in 88 and 32% of
patients class I and II, respectively (P 0.05). The
study demonstrated the need of standardized
decision tools in order to optimize the treatment
&&
of SSTIs [23 ]. In line with this observation, Claeys
et al. [24] reported that 80.4% of ED patients and
74.2% of Observation unit (OU) patients were classi-
fied as CREST class I, whereas Marwick et al. [25] in a
prospective study showed that 89 and 73% of
patients CREST class I and II, respectively, were
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overtreated . Further to these observations Ektare
&
et al. [26 ] demonstrated clearly potential cost
savings with averted hospital admissions ranging
from $13090 to $13473, indicating that hospital
admission and length of stay were the major drivers
of cost in the treatment of ABSSSIs.
Apart from rationalization of healthcare costs,
early response to treatment is an important tool to
guide appropriate antibiotic prescription and esti-
mate future position of the newly launched anti-
bacterials. In the REACH study encompassing 600
real-life patients hospitalized with cSSTIs in 2010–
2011 across Europe, patients without an early
response were more likely to be diabetic, have more
severe disease and harbor difficult-to-treat microor-
ganisms, including gram-negative bacteria and
anaerobes; on the contrary, they experienced more
complications and higher use of healthcare resour-
&&
ces [27 ]. In another recent prospective study of
cellulitis encompassing 216 patients, nonresponse
at day 3 was associated with nonpharmacologic
factors, such as female gender, cardiovascular dis-
ease, higher BMI, shorter duration of symptoms and
nonerysipelas forms of cellulitis. As nonresponse at
day 3 was not attributed to inappropriate treatment,
in contrast to other studies, the authors argue
&&
against automatic-early treatment escalation [28 ]
and call for watchful waiting in selected cases.
Slower response in patients with comorbidities
was also reported in recent randomized controlled
trials [29–34]. Severity of SSTI has been shown to
affect early response in some studies [35] but not in
&& &&
others [27 ,28 ,34]. The significance of assessing
early response to treatment was comprehensively
reviewed by Nathwani et al. [36]. An updated algor-
ithm for the management of SSTIs integrating risk
factors for therapeutic decisions is proposed in
&&
Figure 1 [9,16 ,36].
The most important epidemiological studies in
the last 1–1/2 year, evaluating response to treat-
ment and risk factors for failure and/or recurrences,
& & & &
are shown in Table 3 [21 ,37 ,38,39 ,40,41,42 ,43,
&&
44 ,45]. In a recent meta-analysis of 10 studies,
management failure rate ranged from 15 to 38%,
being more frequent in the presence of fever, elev-
ated inflammatory markers and exposure to MRSA,
thus highlighting once more the importance of
&
widely accepted decision-making tools [46 ]. Failure
to cover for MRSA was also a frequent cause of
&&
recurrence and treatment failure [16 ].
DIAGNOSIS
Diagnosis of uSSTIs such as erysipelas and cellulitis
relies often on clinical features only. Specimens for
culture can be taken in purulent SSTIs or in lesions
www.co-infectiousdiseases.com 161
Skin and soft tissue infections

Inial evaluaon of the paent with SSTI (medical-surgical)

Factors mandang coverage against MDR Does the paent need anmicrobials and which?
Gram-negaves: known colonizaon or
infecon or hospital’s epidemiology, Non-purulent (Necrozing, erysipelas, cellulis) Purulent (Furuncle, carbuncle, abscess)
severely immunocompromised, recent
anbioc exposure and/or history of
hospitalizaon (parcularly ICU), LTCF
resident, postoperave infecon, recent
Moderate: Severe: rule out necrozing Moderate: I& D&Abx (an- Severe: I&D&Abx
travel to endemic countries, sepc shock Mild: Mild: I& D
infecon, start Abx empirically MRSA as definite Rx-Table 2) (an-MRSA empirically-Table 2)
or necrozing infecon parenteral Abx
Per os Abx (Table 2), then adapt to
(Table 2) cultures
?
? Condions
required for non-
Condions requiring
hospitalizaon: symptoms of Yes hospitalizaon:
Does the paent need hospitalizaon? No
systemic infecon, mulorgan No SIRS, or altered
failure, co-morbidies, concern mental status, or
for a deeper or necrozing hemodynamic
Does the paent need OPAT?
infecon, paents non-adherent Long acng i.v. instability
to therapy or severely Daily i.v. treatment Per os
treatment
immunocompromised or failing &
D
MRSA empirically
outpaent treatment Assess for early clinical response (48-72 hours)
Yes No

No improvement Improvement

Consider waing one more Daily i.v. Long acng i.v.

day if paent stable and non- treatment Per os Abx
treatment
pharmacological causes of
slow response present
Suitable for oral Discharge or Consider early
Paent not improving therapy or OPAT? administer a discharge
second dose

Change anmicrobial regimen or
seek for alternave explanaon
Condions required for early discharge and/or OPAT: no posive blood
cultures, improved inflammatory markers and white blood cells, no systemic
signs of infecon, access to primary care and/or day-care hospital services,
ability to shallow and feed, controlled co-morbidies, follow-up scheduled
within 7 days from discharge

FIGURE 1. An algorithm for the management of skin and soft tissue infections, by evaluating early clinical response and the
ability for early discharge with outpatient parenteral or per os antibiotic treatment (adapted from [9,16 ,36]). Abx, &&

antibiotics; I&D, incision and drainage; ICU, intensive care unit; i.v., intravenous; LTCF, long-term care facility; MDR,
multidrug-resistant; MRSA, methicillin-resistance Staphylococcus aureus; OPAT, outpatient parenteral treatment’ Rx: treatment;
SSTIs, skin and soft tissue infections.

undergoing surgical incision and/or debridement or outperforming those of clinical examination (84
imaging-guided drainage [9]. Optimal sampling for and 60%, respectively) [54]. In a study of 32 patients
microbiology is advisable via surgical procedure with ulcers including diabetic foot infections, swab-
from the area of peripheral expansion of the lesion. bing after ultrasonic debridement of the ulcer was
However, in some uSSTIs, surgical incision and equally reliable to biopsy [55]. The use of LRINEC
drainage may be adequate treatment; in a recent score along with ‘a pain out of proportion’ and a
meta-analysis encompassing 1969 patients, the anti- five-fold increase in C-reactive protein (CRP) levels
microbial treatment did not confer any additional may increase the diagnostic threshold for necrotiz-
&
benefit [47 ]. Superficial sampling with swabs and ing fasciitis [56], which remains an important diag-
particularly in chronic-infected ulcers can overesti- nostic challenge in the ED [57].
mate as ‘true pathogens’ microorganisms that
represent colonization. Blood cultures are rarely
positive in SSTIs and are recommended in patients OVERALL MANAGEMENT OF SKIN AND
with underlying comorbidities and systematic SOFT TISSUE INFECTIONS
inflammatory response [9,48]. Recent studies in Recent guidance has been published on the treat-
pediatric patients with uSSTI argue against the ment of SSTIs [9]. Contemporary evidence indicates
necessity of blood cultures as routine practice that early initiation of antibiotics for SSTI at the ED
[49,50]. Accumulating data have emphasized the was associated with significantly better outcomes
&
role of ultrasound applications as an important [42 ,45]. As a general principle, empirical antibiotics
adjunctive diagnostic tool in the management of should target S. pyogenes and S. aureus and cover for
SSTIs in the ED. Ultrasound may guide drainage and MRSA/CA-MRSA and other possible pathogens
microbiological sampling, assessment of disease depending on the clinical features and epidemio-
&&
proliferation and the need for surgical intervention logical risk [9,16 ]. USSTIs represent areas for
and ultimately may contribute to selection of appro- improvement, as clinicians continue prescribing
priate treatment [51–53]. In a prospective study antibiotics (even more than two) postdrainage,
of 151 pediatric patients with SSTI, sensitivity but frequently inactive against MRSA [58]. More-
and specificity of point-of-care ultrasonography over, suboptimal management of SSTIs was reported
for abscesses were 96 and 87%, respectively, in nursing homes [59,60]. Identification and

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 & &
Table 3. Recent studies assessing treatment failure and/or recurrence in skin and soft tissue infections [21 ,37 ,38–45]
Failure or Failure or Factors associated
Author, Study Medical Primary recurrence recurrence with treatment
year design setting Patients (n) outcome Microbiology rate definition failure Abx
&
Lee [37 ] Prospective 14 primary 106 Failure within 90 days S. aureus Overall 22 of 106 (21%) Within 90 days of initial 7 days duration of 76% TMP-SMX, 11%
care clinics from initial visit (13 for MRSA, 9 for visit one of: new infection, lesion doxycycline, 7%
MSSA, P ¼ 0.7) course or change in diameter size 5 cm clindamycin, 9%
antibiotic therapy, cephalexin
additional incision or (overall
drainage, SSTI at a discordance 5%)
new site, SSTI at the
same site, emergency
department visit or
hospital admission
Walsh [38] Retrospective 2 academic medical 163 Appropriateness of Abx 11 MSSA, 10 MRSA, 8 30-day readmission rate 30-day readmission ND ND
centers treatment duration for polymicrobial gram(þ), 6 (6 of 163) secondary to recurrent
SSTIs in hospitalized Streptococci, 4 other SSTI
patients gram(þ), 5 mixed gram
(þ) and gram (–), 3 gram
(–)
&
Haran [39 ] Retrospective 4 emergency 467 Determine if age was ND 12.4% Need for change in Abx, Older age (>65 years), Cephalosporin,
departments associated with surgical intervention higher CCI score, clindamycin,
outpatient department or hospital admission infection involving doxycycline,
treatment failure for within 30 days from hand structures and IV vancomycin,
a
purulent SSTI emergency discharge vancomycin at ED metronidazole,
TMP-SMX,
fluoroquinolones
and azithromycin
Li [40] Retrospective 4 hospitals of a 527 patients Epidemiology and Available for 184 of 527 35 of 527 (6.64%) (20 Reinfection/ ND Various
healthcare hospitalized outcomes of patients (32.5%). Gram (þ) of 527, 3.8% 3 recurrence

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conglomerate with cSSTI hospitalized with 61.41% (MRSA 7.6%), months)
in China cSSTI gram (–) 46.2%
Mistry [41] Retrospective Tertiary care 192 children Clinical failure of OU Available for 105 of 192 43 of 192 (22.4%) One of: unexpected Fever on ED i.v Clindamycin
hospital, ED treatment patients, 66.7% MRSA (primary reason for ward hospitalization presentation, 176, TMP-SMX 3,
department failure was ward directly from OU, ultrasound vancomycin 1,
with 23-h OU admission for 98% of return ED evaluation performance in the ED cefazolin 3 and
cases) within 72 h after OU prior to OU admission other 4
discharge, change in
antibiotic therapy due
to poor clinical
response, need for
incision and drainage
after OU admission
&
May [42 ] Retrospective ED department 197.371 Incidence and factors ND 32.098 (16.3%) had at Repeat SSTI, ED visit Nonsenior adults, female ND
associated with ED least one recurrence, within 6 months from patients, non-Hispanic
visits for recurrent SSTI 10.419 (5.3%) more initial visit white patients,
infections than one recurrence insurance status,
geography and
income, admitted

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patients, higher CCI,
drug or alcohol
abuse, liver disease,

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obesity, history of
drainage or aspiration
Management of skin and soft tissue infections in 2016 Poulakou et al.

163
 164
Table 3 (Continued)
Failure or Failure or Factors associated
Author, Study Medical Primary recurrence recurrence with treatment
year design setting Patients (n) outcome Microbiology rate definition failure Abx
&
Hemmige [21 ] Retrospective Single center 85 Incidence and risk Available for 23 of 85 30 of /85 (35.3%) Recurrent SSTI was Presence of intravascular 20 combination
university of factors for recurrent (mostly S. aureus) at least one recurrent defined as either an catheter, nonhepatitis therapy, 20 b
Chicago medical SSTI among HIV SSTI SSTI at a new site or liver disease, lactam, 21
center’s ID clinic patients during follow up, recurrence at the lymphedema, history clindamycin,
14 of 85 (16.5%) original site greater of IVDU and HIV 8 TMP-SMX, 5
multiple than 30 days after the VL > 1000 c/ml fluoroquinolones,
recurrences initial SSTI, with 3 vancomycin
resolution of the signs and
Skin and soft tissue infections

and symptoms of the 3 no

original infection in the antimicrobials
interim
Macia-Rodriguez Retrospective Single center 308 hospitalized Factors associated Local cultures performed for 34 of 308 Readmission for SSTI Presence of malignancy 33.1% amoxicillin/
[43] university hospital patients with mortality 144 patients, 95 of 144 readmitted for within 6 months from and clavulanate, 26%

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and readmissions were positive, 66 of 95 SSTI within discharge immunosuppression cloxacillin and
gram (þ) (MRSA 11 of 6 months from 29.5%
66), 53 of 95 gram (–), discharge combination
11 of 95 anaerobes
&&
Eells [44 ] Prospective Tertiary care hospital 87 patients with Clinical response after S. aureus 40 of 87 (46%) Any of the following: Poor adherence to 46 TMP-SMX, 29
S. aureus skin 30 days of follow up relapse of skin postdischarge clindamycin, 4
infection without infection, new skin antibiotic therapy, amoxicillin-
bacteremia, infection, receipt of diabetes and illicit clavulanate, 3
osteomyelitis, prolonged antibiotic drug use linezolid, 2
endocarditis or therapy for skin cephalexin, 1
hardware- infection, receipt of dicloxacillin and
associated new antibiotic therapy 1 doxycycline
infection or change in therapy
for skin infection, new
incision and drainage
May [45] Subanalysis of a 2 EDs Patients treated Failure to improve within 27.5% MRSA, 18.7% Combined SSTI Failure defined as no Previous contact with 7.3% b lactams,
parent study for a cutaneous 1 week following MSSA, 47.7% other, recurrence change in/or someone infected with 39.4%
abscess with initial treatment, SSTI 6.2% no growth/missing occurred in increased pain, MRSA, history of SSTI clindamycin,
incision and recurrence at 1 and/ 28% of 193 swelling, erythema, within the past 12 17.6% TMP-SMX,
drainage. 193 or 3 months of patients drainage of the months and clinician 9.8% TMP-SMX þ
completed either treatment of the index current abscess or use of wound packing b lactams, 1%
1- or 3-month infection new or persistent other and 24.9%
follow up fever. Recurrence none
defined as the
presence of a new
abscess at the same
or different locations
at least 2 weeks after
resolution of the initial
abscess

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a
Vancomycin as one-time dose in ED was associated with worse patient outcome. Maybe in part due to the frequency that vancomycin is under dosed in ED. Also, it was not followed with MRSA antibiotics for home in
&
one out of three patients treated [39 ].
Abx, antibiotic; CCI, Charlson comorbidity index; ED, emergency department; ID, infectious disease; IV, intravenous; IVDU, intravenous drug use; MRSA, methicillin-resistant Staphylococcus aureus; MSSA, methicillin-
sensitive Staphylococcus aureus; ND, not defined; OU, observation unit; SSTI, soft skin tissue infection; TMP-SMX, trimethoprim/sulfamethoxazole.
& &
Adapted from [21 ,37 ,38–45].

Volume 30  Number 2  April 2017


management of SSTIs in ICU-admitted patients is
completely different from community-acquired
counterparts and MDR bacteria should be con-
sidered [61]. Outpatient parenteral treatment
(OPAT) also needs attention, as more than 70% of
OPAT patients administered vancomycin for SSTIs
had subtherapeutic drug levels [62]. On the con-
trary, OPAT with daptomycin was safe [63], whereas
daptomycin dosing exceeding 6 mg/kg/day in more
than 1000 inpatients within the EU-CORE study
was proven safe [64]. A large-scale pharmacokinetic
study across 12 European countries revealed the risk
of suboptimal treatment of MRSA in cSSTIs with
more than 40% of patients on vancomycin receiving
inadequate dose, whereas the majority of patients
administered first-line teicoplanin and daptomycin
(96 and 80%, respectively) received higher than
&&
labeled cSSTI doses [65 ]. Wise selection of candi-
dates for outpatient treatment and transition from
i.v. to oral treatment is very important to avoid
&&
irrational healthcare expenditures [23 ,26 ]. Of
note, poor adherence to oral, postdischarge anti-
biotic treatment for staphylococcal SSTIs was
&&
associated with treatment failure [44 ]. A Cochrane
analysis including nine Randomised-controlled
trials (RCTs) showed a better outcome and shorter
length of hospital stay with linezolid than with
vancomycin, but results are prone to biases [66 ].
An RCT showed superiority of a 7-day treatment
with trimethoprim 320 mg/sulphomethoxazole
1600 mg over placebo for uSSTIs: increased clinical
cure, reduction of surgical drainage and reinfections
(per protocol [PP] 7.2; 95% confidence interval [CI],
3.2–11.2; P < 0.001, PP 5.2; 95% CI, 8.2 to 2.2)
and (PP 7.2 s; 95% CI, –10.4 to –4.1) respectively
&
[67 ]. Tigecycline alone or in combinations with
other antimicrobials was demonstrated effective in
50 patients with necrotizing SSTIs within 163
patients with complicated SSTIs [68] as well as in
abdominal skin infections [69]. A retrospective mul-
ticenter study across 12 European centers in patients
with peripheral vascular disease and/or diabetes
showed significant benefit of linezolid over vanco-
mycin in terms of hospital stay and treatment
& &
duration [70 ].
Management of uSSTIs is a perfect target for
antimicrobial stewardship interventions, as an over-
coverage of gram negatives and anaerobes has been
empirically initiated in almost half of SSTIs’ adult
&&
hospitalized patients [23 ,24,25,38].
NOVEL ANTIMICROBIAL THERAPY
Novel antibacterial agents against gram-positive
bacteria causing ABSSTI (including MRSA strains)
have been developed over the last few years in
0951-7375 Copyright ß 2017 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.
Management of skin and soft tissue infections in 2016 Poulakou et al.
&&
agents [1,2,27 ]. With currently available arma-
mentarium, clinicians not only need to reevaluate
their current treatment paradigms but moreover,
using the new guidance can determine patient
groups most suitable for early de-escalation or
switch to oral therapy [9,10,36]. As inadequate treat-
ment of MRSA infections may lead to recurrence
&&
[16 ,71], newly launched antimicrobials such as
oritavancin, dalbavancin and tedizolid may obviate
this risk [72,73].
Several benefits of some of the drugs currently
under active investigation for ABSSSI exist. As com-
pared to older agents, e.g. vancomycin, linezolid
and daptomycin, the new agents have equal efficacy
& &
and are given for shorter intervals [74 ,75 ] or have a
& &
better safety profile [75 ,76 ,77] (Table 1). Single-
dose regimens have been proven efficacious for
& &&
oritavancin [76 ] and dalbavancin [78 ] with a
favorable safety profile compared with vancomycin
&
or linezolid [30,75 ]. Safety may become an import-
&
ant issue in selecting appropriate therapy in ABSSSI;
whereas daptomycin use has been associated with
&
very successful clinical outcomes [79 ], monitoring
for creatine phosphokinase elevations is necessary
and in some instances eosinophilic pneumonia has
developed [80]. Linezolid use may be limited by
hematological side-effects [81,82]. The novel oxazo-
&
lidinone tedizolid exhibits an excellent activity
against most gram-positive pathogens associated
with ABSSSI [30] including linezolid nonsusceptible
strains [83] while exhibiting a much better hemato-
&
logical side-effect profile [76 ]; thus, it could serve as
an alternative to linezolid.
Antibacterials may differ regarding their bacteri-
cidal activity against specific pathogens like MRSA
or enterococci, especially resistant strains. In a very
recent study, among new antibacterials used in
ABSSSI, rapid bactericidal activity for MRSA isolates
has been shown for dalbavancin and daptomycin
irrespective of bacterial burden [84].
In a study of cSSTIs, ceftaroline fosamil use was
associated with lower length of stay, equivalent
or lower in-hospital mortality rates and lower
inpatient costs compared with usual practice
(including linezolid) [85 ]. Dosing concerns are
under investigation suggesting that a t.i.d. admin-
istration can better achieve the pk/pd goals also for
&& & &
pediatric patients [86 ,87 ,88 ]. Hematological
disturbances and skin rash were the common
adverse reactions of ceftaroline in a recent evalu-
ation, but without increased rates in b-lactam
&
hypersensitive patients [89 ].
Thus, the clinician should carefully evaluate the
clinical scenario in order to reach the appropriate
therapeutic decision especially in difficult infections
due to resistant pathogens, taking into account
www.co-infectiousdiseases.com 165
 166
Table 4. Update of information about novel antimicrobials for ABSSSI according to activity, administration route, indications and market status (marketed to phase II agents
from top to the bottom part of the table)
Activity Studies/
Antibacterial Class vs. gram (–) Gram (þ) spectrum indications Administration Dose Status, comments

Ceftaroline Cephalosporin Yes MSSA, MRSA, S. pyogenes, ABSSSI, CABP iv only, q12 h 600 mg Marketed, direct Coombs test
S. agalactiae, Streptococcus regimen, over seroconversion, watch for
&
anginosus group S. 5–60 min hypersensitivity reactions [89 ],
dysgalactiae adjustment for Cr clearance,
q8 h regimen for patients with
evidence of systemic
Skin and soft tissue infections

inflammation and/or
&
comorbidities [85 ]
Oritavancin Semisynthetic No S. aureus, MRSA, VISA, ABSSSI iv only, 1 dose 1200 mg Marketed, bactericidal, CYP450
[92] lipoglycopeptide VRSA, GAS, S. anginosus, over 3 h interactions [93], give warfarin

www.co-infectiousdiseases.com
E. faecalis, E. Faecium/VRE 12 h after, FDA warning re:
(Van A,B,C,D) osteomyelitis, new formulation,
may lead to early discharge
Dalbavancin Lipoglycopeptide No S. aureus, MRSA (low MICs), ABSSSI iv, 1 dose over 1000 mg then Marketed, bactericidal decrease
[94] VISA, GAS, Enterococci 30 min 500 mg q 7 days; dose to 25% for creatinine
(inactive against Van A) 1500 mg once clearance < 30 ml/min, not
dialyzable, case reports in BSI,
PJI [95], may lead to early
discharge
Tedizolid [83] Oxazolidinone No S. aureus, MRSA, VISA, GAS, ABSSSI iv and oral, once 200 mg Marketed, no dose adjustment for
prodrug S. anginosus group, S. daily for 6 age, renal/hepatic impairment,
agalactiae, E. faecalis days better hematological profile
(vancomycin susceptible than linezolid, ongoing studies
only) for HABP, VAP, may lead to
early discharge with iv to per
os switch
Fusidic acid Fusidane, bacterial No MSSA, MRSA, higher MICs ABSSSI, PJI Oral, twice a Phase II study Phase III for ABSSSI in USA, use
elongation factor for streptococci and daily regimen regimen, in combination with rifampin for
inhibitor [96] enterococci 1500 mg CEM- PJI97], resistance development
102 loading should be monitored [98]
dose, then
600 mg bid 
10–14 days
Iclaprim Dihydrofolate Yes MSSA, MRSA, GAS, S. ABSSSI, HABP iv over 2 h, twice 80 mg Phase III. Active against TMP-

Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.

[99,100] reductase pneumoniae daily resistant bacteria, Ongoing
inhibitor ABSSSI studies (REVIVE 1,2)
[101,102]
Lefamulin Pleuromutilin, Yes MSSA, MRSA, CoN Staph, ABSSSI, CABP Oral, q12 h iv 600 mg; 150 mg Phase III, planned indications
[103,104] protein synthesis GAS, VRE g12 h, over ABSSI, studies on CABP
inhibitor 60 min ongoing [107]
[105,106]

Volume 30  Number 2  April 2017

 Table 4 (Continued)

Activity Studies/
Antibacterial Class vs. gram (–) Gram (þ) spectrum indications Administration Dose Status, comments

Omadacycline Tetracyclines Yes MSSA, MRSA, GAS, group B CABP, ABSSSI, Oral Phase III studies ongoing or
[108] (9-amino- streptococci, VRE [110] cUTI completed [111,112]
methylcycline)
[109]
Delafloxacin Fluoroquinolone Yes MSSA, MRSA, Streptococci, ABSSSI, CABP Oral Phase II study in ABSSSI
[113] Enterococci [113] published, with cure rates better
than vancomycin and similar to
linezolid [114]. Phase III for
ABSSSI completed [115]
CG-400549 Enoyl-ACP reductase Yes, E. coli not Staphylococci-specific, MSSA, ABSSSI, Oral Phase II study completed [118]
(Fabl) inhibitor Pseudomonas MRSA, not Enterococci osteomyelitis
[116,117] spp
Debio 1450 Fabl inhibitor, Debio No Staphylococci specific, ABSSSI, iv, oral Phase II study completed [119]
1452 prodrug including MDR (VISA, osteomyelitis
daptomycin or linezolid-
resistant strains)
Brilacidin Defensin mimetic No Staphylococci, b-hemolytic ABSSSI Iv Phase II completed [121]

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[120] Streptococci and E. faecium
MRX-I Oxazolidinone No MSSA, MRSA and VRE [122] ABSSSI Oral Phase II active, not recruiting
[123] same or better efficacy
than linezolid in both systemic
and local infection models
[122]
Nemonoxacin Quinolone Yes MSSA, MRSA and CABP, DFI, Oral Phase II on diabetic foot infections
E. faecalis [124,125] ABSSSI completed [126], more active
than levofloxacin and
moxifloxacin against Gram (þ)
cocci [127], ongoing CABP
studies

ABSSSIs, acute bacterial skin and skin structure infections; CABP, community-acquired bacterial pneumonia; cUTI, complicate urinary tract infection; GAS, group A streptococcus; HABP, hospital acquired bacterial
pneumonia; MRSA, methicillin-resistant S. aureus; MSSA, methicillin susceptible S. aureus; PJIs, prosthetic joint infections; VRE, vancomycin-resistant enterococci.
& &

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Adapted from [83,85 ,89 ,92–127].

www.co-infectiousdiseases.com
Management of skin and soft tissue infections in 2016 Poulakou et al.

167
Skin and soft tissue infections
accumulating evidence about particular antibiotic
&&
properties, safety and cost [16 ,90].
NON-ANTIMICROBIAL THERAPY WITH
VACCINES-PHAGES
Bacteriophages (phages), against specific bacteria,
are a promising novel therapeutic tool for ABSSSI
or chronic skin infections that have not been exten-
sively studied so far. A S.aureus-specific phage was
successfully applied topically in a series of patients
with chronic diabetic foot infections on ulcerated
toes with osteomyelitis in a recent trial providing
the groundwork for future randomized controlled
clinical trials [91].
Characteristics of agents in study or recently
introduced in clinical practice are summarized in
& &
Table 4 [83,85 ,89 ,92–127].
CONCLUSION
ABSSSIs are one of the most common causes of
ambulatory visits and represent a substantial per-
centage of admissions in medical and – to a lesser
extent – in surgical wards. Despite the availability of
many antimicrobials with antistaphylococcal
activity including some newly launched antibiotics,
S. aureus remains the cardinal pathogen in ABSSSIs;
treatment challenges derive mainly because of the
expansion of MRSA (including both CA-MRSA and
Hospital-acquired MRSA). Many recent studies focus
on early recognition of risk factors for relapse or
failure of treatment and early assessment of clinical
response to guide de-escalation and early hospital
discharge. Current literature indicates that properly
constructed algorithms should be adopted in the
EDs, to select the correct patient for outpatient
treatment and recognize early those with risk factors
for nonresponse. In this context, except for disease
severity and extent, nonpharmacologic parameters
such as comorbidities should be taken into account.
The addition of new long-acting antibacterials in
the current armamentarium offers new possibilities
for outpatient management of ABSSSIs and health-
care cost reduction. Prospective studies are import-
ant to clearly delineate the use of new antibiotics
with anti-MRSA activity in future practice. Novel
approaches such as phage therapy are promising and
may completely change the therapeutic field of
SSTIs in the future.
Acknowledgements
We would like to thank Dr George Siakallis for the
assistance in this article.
Financial support and sponsorship
This work was not financially supported or sponsored.
168 www.co-infectiousdiseases.com
Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.
Conflicts of interest
G.P. has received honoraria from MSD and Pfizer. S.T.
has received honoraria from Merck. E.G. has received
honoraria from Novartis.
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